title: Metabolomic signatures of aggressive prostate cancer.
abstract: BACKGROUND
  Current diagnostic techniques have increased the detection of prostate cancer; however, these tools inadequately stratify patients to minimize mortality. Recent studies have identified a biochemical signature of prostate cancer metastasis, including increased sarcosine abundance. This study examined the association of tissue metabolites with other clinically significant findings.
  
  
  METHODS
  A state of the art metabolomics platform analyzed prostatectomy tissues (331 prostate tumor, 178 cancer-free prostate tissues) from two independent sites. Biochemicals were analyzed by gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-tandem mass spectrometry. Statistical analyses identified metabolites associated with cancer aggressiveness: Gleason score, extracapsular extension, and seminal vesicle and lymph node involvement.
  
  
  RESULTS
  Prostate tumors had significantly altered metabolite profiles compared to cancer-free prostate tissues, including biochemicals associated with cell growth, energetics, stress, and loss of prostate-specific biochemistry. Many metabolites were further associated with clinical findings of aggressive disease. Aggressiveness-associated metabolites stratified prostate tumor tissues with high abundances of compounds associated with normal prostate function (e.g., citrate and polyamines) from more clinically advanced prostate tumors. These aggressive prostate tumors were further subdivided by abundance profiles of metabolites including NAD+ and kynurenine. When added to multiparametric nomograms, metabolites improved prediction of organ confinement (AUROC from 0.53 to 0.62) and 5-year recurrence (AUROC from 0.53 to 0.64).
  
  
  CONCLUSIONS
  These findings support and extend earlier metabolomic studies in prostate cancer and studies where metabolic enzymes have been associated with carcinogenesis and/or outcome. Furthermore, these data suggest that panels of analytes may be valuable to translate metabolomic findings to clinically useful diagnostic tests.
authors.affiliation: Clinical Research and Development, Metabolon, Inc., Durham, North Carolina, USA. jmcdunn@metabolon.com
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Adam
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Neri
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wolfert
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wheeler
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D055432:Metabolomics; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness / Q000175:diagnosis; D009362:Neoplasm Metastasis / Q000175:diagnosis*; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis; D011237:Predictive Value of Tests; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012189:Retrospective Studies; D012521:Sarcosine / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D017430:Prostate-Specific Antigen; D012521:Sarcosine
keywords: clinical heterogeneity; diagnosis; metabolomics; prostate cancer